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Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 ​at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p ​= ​0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p ​= ​0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67–5.7; p ​= ​0.006 and HR 2.04, 25%CI 1.22–3.35; p ​= ​0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04–4.87; p ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.

Abstract Background Non-alcoholic fatty liver disease (NAFLD), identified by the Fatty Liver Index (FLI), is associated with increased mortality and cardiovascular (CV) outcomes. Whether this also applies to type 1 diabetes (T1D) has not been yet reported. Methods We prospectively observed 774 subjects with type 1 diabetes (males 52%, 30.3 ± 11.1 years old, diabetes duration (DD) 18.5 ± 11.6 years, HbA1c 7.8 ± 1.2%) to assess the associations between FLI (based on BMI, waist circumference, gamma-glutamyl transferase and triglycerides) and all-cause death and first CV events. Results Over a median 11-year follow-up, 57 subjects died (7.4%) and 49 CV events (6.7%) occurred among 736 individuals with retrievable incidence data. At baseline, FLI was

Semantic web technologies (SWT) represent data in a format that is easier for machines to understand. Validating the knowledge in data graphs created using SWT is critical to ensure that the axioms accurately represent the so-called “real” world. However, data graph validation is a significant challenge in the semantic web domain. The Shapes Constraint Language (SHACL) is the latest W3C standard developed with the goal of validating data-graphs. SHACL (pronounced as shackle) is a relatively new standard and hitherto has predominantly been employed to validate generic data graphs like WikiData and DBPedia. In generic data graphs, the name of a class does not affect the shape of a class, but this is not the case with biomedical ontology data graphs. The shapes of classes in biomedical ontology data graphs are highly influenced by the names of the classes, and the SHACL shape creation methods developed for generic data graphs fail to consider this characteristic difference. Thus, the existing SHACL shape creation methods do not perform well for domain-specific biomedical ontology data graphs. Maintaining the quality of biomedical ontology data graphs is crucial to ensure accurate analysis in safety-critical applications like Electronic Health Record (EHR) systems referencing such data graphs. Thus, in this work, we present a novel method to create enhanced SHACL shapes that consider the aforementioned characteristic difference to better validate biomedical ontology data graphs. We leverage the knowledge available from lexical auditing techniques for biomedical ontologies and incorporate this knowledge to create smart SHACL shapes. We also create SHACL shapes (baseline SHACL graph) without incorporating the lexical knowledge of the class names, as is performed by existing methods, and compare the performance of our enhanced SHACL shapes with the baseline SHACL shapes. The results demonstrate that the enhanced SHACL shapes augmented with lexical knowledge of the class names identified 176 violations which the baseline SHACL shapes, void of this lexical knowledge, failed to detect. Thus, the enhanced SHACL shapes presented in this work significantly improve the validation performance of biomedical ontology data graphs, thereby reducing the errors present in such data graphs and ensuring safe use in the life-critical applications referencing them.

Abstract Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome‐wide CRISPR‐Cas9 knockout screen, which revealed the LKB1‐SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria‐targeted antioxidant promotes enhanced cell death efficacy in LKB1‐ and SIK2‐negative uveal melanoma cells compared to control cells. Our study also identified an LKB1‐loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.

Abstract Penile traumatic injuries are rare with potentially severe consequences, with clinical assessment challenging due to pain and swelling. Ultrasound is the primary imaging modality for assessing the penis. It has a high spatial resolution and rapid availability and is portable. Contrast enhanced ultrasound is an advanced ultrasound technique that adds real-time dynamic vascular imaging safely, increasing diagnostic precision and confidence, allowing for better therapeutic management of traumatic penile injuries. Contrast enhanced ultrasound helps to delineate the extent of a haematoma, distinguishing this from the herniated corpus cavernosum, detecting the point of rupture of the tunica albuginea, showing vascular abnormalities, localising a dislocated penis and determining penile viability. The integrity of the urethra may be assessed with intracavitary contrast enhanced ultrasound. Additionally, contrast enhanced ultrasound allows monitoring of the response to endovascular and surgical treatment. This review aims to detail the anatomy and pathogenesis of penile trauma, to give guidance on optimising the contrast enhanced ultrasound technique and to obtain diagnostic examinations. Illustration of the spectrum of aspects of penile trauma will be complemented with a literature review. Critical relevance statement Contrast enhanced ultrasound is a safe and efficient imaging modality that allows for highly accurate diagnoses, helping achieve more successful and conservative treatments of penile trauma complications. Key points • Ultrasound is an accurate and safe imaging test for penile trauma. • CEUS adds dynamic vascular imaging in real-time increasing diagnostic confidence. • CEUS can delineate penile haematomas, locate fractures and demonstrate vessel integrity. • CEUS potentially allows for more conservative treatment of penile trauma complications. Graphical Abstract

Over the past thirty years, the red gorgonian Paramuricea clavata in the Mediterranean Sea has faced increasing threats, including heat waves and human activities such as artisanal and recreational fishing. Epibiosis on damaged gorgonian colonies is generally used as an indirect indication of stressed conditions. The density and height of P. clavata and the percentage of colonies affected by epibiosis and entangled in lost fishing gear were monitored to investigate the phenomenon and its trend over time in the Ligurian Sea. Analyses were based on transects collected during ROV campaigns between 2015 and 2022 at depths of 33–90 m. A strong correlation was observed between fishing efforts in the study area and the level of epibiosis. Maximal percentages of colonies affected by epibiosis and entanglement were recorded at depths of 50–70 m. Temporally, marine heat waves before 2019 were identified as the primary cause of damage to P. clavata. The decrease in epibiosis percentages after 2019, despite the 2022 heat wave, may be due to a quick recovery ability of the populations and a reduction in fishing activities during the COVID-19 lockdown in 2020. Long-term monitoring programmes are essential to understand the changes in marine benthic communities exposed to different stressors.

Abstract Background The Multiple Sclerosis Quality of Life-54 (MSQOL-54) is one of the most commonly-used MS-specific health-related quality of life (HRQOL) measures. It is a multidimensional, MS-specific HRQOL inventory, which includes the generic SF-36 core items, supplemented with 18 MS-targeted items. Availability of an adaptive short version providing immediate item scoring may improve instrument usability and validity. However, multidimensional computerized adaptive testing (MCAT) has not been previously applied to MSQOL-54 items. We thus aimed to apply MCAT to the MSQOL-54 and assess its performance. Methods Responses from a large international sample of 3669 MS patients were assessed. We calibrated 52 (of the 54) items using bifactor graded response model (10 group factors and one general HRQOL factor). Then, eight simulations were run with different termination criteria: standard errors (SE) for the general factor and group factors set to different values, and change in factor estimates from one item to the next set at

Abstract Background The participation of health professionals in designing interventions is considered vital to effective implementation, yet in areas such as clinical coordination is rarely promoted and evaluated. This study, part of Equity-LA II, aims to analyse the design process of interventions to improve clinical coordination, taking a participatory-action-research (PAR) approach, in healthcare networks of Argentina, Brazil, Chile, Colombia, Mexico and Uruguay. This participatory process was planned in four phases, led by a local steering committee (LSC): (1) dissemination of problem analysis results and creation of professionals’ platform, (2) selection of problems and intervention (3) intervention design and planning (4) adjustments after evaluation of first implementation stage. Methods A descriptive qualitative study based on documentary analysis, using a topic guide, was conducted in each intervention network. Documents produced regarding the intervention design process were selected. Thematic content analysis was conducted, generating mixed categories taken from the topic guide and identified from data. Main categories were LSC characteristics, type of design process (phases, participants’ roles, methods) and associated difficulties, coordination problems and interventions selected. Results LSCs of similar composition (managers, professionals and researchers) were established, with increasing membership in Chile and high turnover in Argentina, Colombia and Mexico. Following results dissemination and selection of problems and interventions (more participatory in Chile and Colombia: 200–479 participants), the interventions were designed and planned, resulting in three different types of processes: (1) short initial design with adjustments after first implementation stage, in Colombia, Brazil and Mexico; (2) longer, more participatory process, with multiple cycles of action/reflection and pilot tests, in Chile; (3) open-ended design for ongoing adaptation, in Argentina and Uruguay. Professionals’ time and the political cycle were the main barriers to participation. The clinical coordination problem selected was limited communication between primary and secondary care doctors. To address it, through discussions guided by context and feasibility criteria, interventions based on mutual feedback were selected. Conclusions As expected in a flexible PAR process, its rollout differed across countries in participation and PAR cycles. Results show that PAR can help to design interventions adapted to context and offers lessons that can be applied in other contexts.

ABSTRACTImmune-checkpoint inhibitors (ICI) are highly effective in reinvigorating T cells to attack cancer. Nevertheless, a large subset of patients fails to benefit from ICI, partly due to lack of the cancer neoepitopes necessary to trigger an immune response. In this study, we used the thiopurine 6-thioguanine (6TG) to induce random mutations and thus increase the level of neoepitopes presented by tumor cells. Thiopurines are prodrugs which are converted into thioguanine nucleotides that are incorporated into DNA (DNA-TG), where they can induce mutation through single nucleotide mismatching. In a pre-clinical mouse model of a mutation-low melanoma cell line, we demonstrated that 6TG induced clinical-grade DNA-TG integration resulting in an improved tumor control that was strongly T cell dependent. 6TG exposure increased the tumor mutational burden, without affecting tumor cell proliferation and cell death. Moreover, 6TG treatment re-shaped the tumor microenvironment by increasing T and NK immune cells, making the tumors more responsive to immune-checkpoint blockade. We further validated that 6TG exposure improved tumor control in additional mouse models of melanoma. These findings have paved the way for a phase I/II clinical trial that explores whether treatment with thiopurines can increase the proportion of otherwise treatment-resistant cancer patients who may benefit from ICI therapy (NCT05276284).

There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies.

ObjectiveThis study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS).MethodsWe retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.ResultsOf 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (

Abstract Introduction B-cell-depleting agents have been widely used for neuromyelitis optica spectrum disorder (NMOSD) and MOG-associated diseases (MOGAD), but no consensus exists on the optimal dose and frequency of treatment administration. The aim of our study was to evaluate the effect of a Rituximab (RTX) personalized treatment approach based on CD27-positive B-cell monitoring on efficacy, safety, and infusion rates. Methods This is a retrospective, uncontrolled, single-center study including patients with NMOSD and MOGAD treated with RTX at a tertiary multiple sclerosis center at the San Luigi University Hospital, Orbassano, Italy. All the patients were treated with RTX induction, followed by maintenance infusion at the dosage of 1000 mg according to cell repopulation: initially according to total CD19-positive B-cell monitoring (> 0.1% of lymphocytes), and subsequently according to CD27-positive B-cell repopulation (> 0.05% of lymphocytes for the first 2 years, and subsequently > 0.1%). NMOSD and MOGAD activity was assessed as clinical or MRI activity. All patients were screened of the occurrence of severe adverse events (AEs). Results A total of 19 patients were included in the analysis. Median follow-up was 7.64 years (range 3.09–16.25). The annualized relapse rate (ARR) 1 year before RTX start was 2.37 [Standard deviation (SD), 1.34] and decreased to 0.08 (SD 0.11) in the subsequent years after RTX initiation. ARR did not differ before and after start of CD27 monitoring. Median inter-dose time was 8.80 (range 5.78–14.23) before CD27 monitoring and 15.93 months (range 8.56–35.37) after CD27 monitoring (p

Summary: Super-enhancers (SEs) are stretches of enhancers ensuring a high level of expression of key genes associated with cell function. The identification of cancer-specific SE-driven genes is a powerful means for the development of innovative therapeutic strategies. Here, we identify a MITF/SOX10/TFIIH-dependent SE promoting the expression of BAHCC1 in a broad panel of melanoma cells. BAHCC1 is highly expressed in metastatic melanoma and is required for tumor engraftment, growth, and dissemination. Integrative genomics analyses reveal that BAHCC1 is a transcriptional regulator controlling expression of E2F/KLF-dependent cell-cycle and DNA-repair genes. BAHCC1 associates with BRG1-containing remodeling complexes at the promoters of these genes. BAHCC1 silencing leads to decreased cell proliferation and delayed DNA repair. Consequently, BAHCC1 deficiency cooperates with PARP inhibition to induce melanoma cell death. Our study identifies BAHCC1 as an SE-driven gene expressed in melanoma and demonstrates how its inhibition can be exploited as a therapeutic target.

La emergencia sanitaria COVID-19 impactó en los/as trabajadores de salud, dejando en evidencia: el malestar subjetivo y altos índices de ansiedad y depresión. El objetivo del presente trabajo es analizar las experiencias y vivencias de trabajadores/as de la salud durante la pandemia. La misma se realizó a partir del análisis de las respuestas obtenidas en la pregunta abierta del formulario autoadministrado del proyecto Héroes Uruguay. La población objetivo fue el personal de los servicios de salud integrados al Sistema Nacional Integrado de Salud en los tres niveles de atención. Las respuestas fueron agrupadas y categorizadas en base a su frecuencia. La categoría condiciones de trabajo fue la temática más mencionada, seguida de organización del trabajo y vivencias. Realizamos otra categorización sobre los sentidos subjetivos durante la pandemia, nueve categorías son las frecuentes, siendo el 86% de los sentidos subjetivos: ansiedad y estrés, miedo, cansancio, no apoyo social y sobrecarga son los más mencionados. Los resultados muestran que la mayoría de las respuestas remite a las condiciones y a la organización del trabajo, se trata de dimensiones claves en la salud del trabajador, en su entorno, y en los procesos de asistencia al paciente y su familia. Este estudio nos permite afirmar la importancia a nivel organizacional y de políticas de salud, de generar entornos laborales seguros y saludables. La emergencia sanitaria generada por el COVID 19, expuso y agudizó la tensión de los sistemas sanitarios y su impacto en la salud y bienestar del personal.

State-of-the-art remote sensing image management systems adopt scalable databases and employ sophisticated indexing techniques to perform window and containment queries. Many rely on space-filling curve (SFC) based index techniques designed for key-value databases and are predominantly employable for images that are iso-oriented. Critically, these indexes do not consider the high degree of overlap among images that exists in many data sets and the affiliated storage requirements. Specifically, employing an SFC-based grid cell index approach in consort with ground footprint coverage of the images requires storage of a unique image object identification (IOI) for each image in every grid cell where overlap occurs. Such an approach adversely affects both storage and query response times. In response, this paper presents an optimization technique for an SFC-based grid cell space indexing. The optimization is specifically designed for window and containment queries where the region of interest overlaps with at least a 2 × 2 grid of cells. The technique is based on four cell removal steps, thus called “four step algorithm” (4SA). Each step employs a unique spatial configuration to check for continuous spatial extent. If present, the IOI of the target cell is omitted from further consideration. Analysis and experiments on real world and synthetic image data demonstrated that 4SA improved storage demands by 41.3% – 47.8%. Furthermore, in the performed querying experiments, only 42% of IOI elements needed to be processed, thus yielding a 58% productivity gain. The reduction of IOI elements in querying also impacted the CPU execution time (3.0% – 5.2%). The 4SA also demonstrated data scalability and concurrent user scalability in querying large regions by completing the index searching and concurrent user scalability 1.86% – 3.35% faster than when 4SA was not applied.

Magnetic resonance imaging (MRI) was shown to be a viable method for graft healing evaluation. Platelet-rich fibrin (PRF) was found to speed up bone graft healing process. Sinus lift surgery outcomes after healing period are usually performed with computerized tomography that is not capable to describe graft vascularization and exposes patient to ionizing radiation. The objective of this study is to propose contrast-enhanced magnetic resonance imaging (CE-MRI) as a promising method for the in vivo assessment of sinus lift grafting procedures. A bilateral sinus augmentation surgery was performed. Left sinus was grafted only with bovine deproteinized bone mixed in a 1:1 ratio with autologous bone, in the right sinus, the same biomaterials with the addition of platelet-rich fibrin (PRF) were applied. CE-MRI was performed to evaluate angiogenesis before surgery and at 11, 25, 53, and 104 days after surgery. At 6 months (T0) and after 10 years (T1), before dental implants insertion, bone biopsies were performed and analysed quantitatively. Left sinus graft showed a centripetal pattern of angiogenesis, with the central region remaining unvascularized at 104 days post-surgery. Right side showed a wider and homogeneous vascularization from 25 days after surgery. At T0 new bone formation was only peripheral in the left sinus, whereas it developed both peripherally and through biomaterial in the right sinus. At T1 particles of biomaterial were still present in left sinus, while in right sinus they were not. CE-MRI offers quantitative parameters to evaluate vascularization of biomaterials. The addition of PRF promotes an early development of a widespread vascular system.

Fingolimod (FTY720) and siponimod (BAF312) are selective agonists for sphingosine-1-phosphate (S1P) receptors approved for the treatment of relapsing–remitting (RR) and secondary progressive (SP) multiple sclerosis (MS), respectively. BAF312 exerts pro-myelination and neuro-protective functions on CNS resident cells, although the underlying molecular mechanism is not yet fully understood. NR4A2 is an anti-inflammatory gene, belonging to the NR4A family, whose expression is reduced in blood from treatment-naïve patients with RRMS, but is restored in patients treated with FTY720 for more than two years. We performed an in vitro study to investigate the potential involvement of the NR4A genes in the protective and restorative effects of BAF312. We showed that BAF312 enhances the expression of NR4A1 and NR4A2 in the N9 microglial cell line, but has no effect in the peripheral blood mononuclear cells and oligodendrocytes. This study suggests a novel molecular mechanism of action for the selective agonists for S1P receptors within the CNS.

The MITF transcription factor directly binds to the kinase domain of RAF kinases, including ARAF, BRAF and CRAF in melanoma cells. RAF/MITF complex promotes cytoplasmic accumulation of MITF and thus negatively regulates its transcriptional activity.

Melanocytes are located in various parts of the human body, such as the skin and the eye. Their transformation leads to melanoma, an aggressive and deadly neoplasm. Cutaneous and uveal melanomas show different characteristics, including significant differences in genetic alterations, metastatic sites and therapeutic response. In recent decades, great efforts have been made to obtain a more comprehensive understanding of genetics, genomics and molecular changes, enabling the identification of key cellular processes and signaling pathways in melanomas. Major breakthroughs were realized in the treatment of metastatic cutaneous melanoma, but most patients relapse. Currently, there is no approved systemic treatment for metastatic uveal melanoma. Thus, these two different cancers are in therapeutic need to overcome treatment failure and improve patient prognosis. In this review we discuss on one hand the mutation of MITF, the master gene of melanocyte homeostasis, which we identified as a new melanoma predisposition gene in cutaneous melanoma, and on the other hand the recent findings of intratumor heterogeneity and characterization of cell sub-populations in primary uveal melanomas. These studies offer new tools for early detection and therapeutic targets.

Point density is an important property that dictates the usability of a point cloud data set. This paper introduces an efficient, scalable, parallel algorithm for computing the local point density index, a sophisticated point cloud density metric. Computing the local point density index is non-trivial, because this computation involves a neighbour search that is required for each, individual point in the potentially large, input point cloud. Most existing algorithms and software are incapable of computing point density at scale. Therefore, the algorithm introduced in this paper aims to address both the needed computational efficiency and scalability for considering this factor in large, modern point clouds such as those collected in national or regional scans. The proposed algorithm is composed of two stages. In stage 1, a point-level, parallel processing step is performed to partition an unstructured input point cloud into partially overlapping, buffered tiles. A buffer is provided around each tile so that the data partitioning does not introduce spatial discontinuity into the final results. In stage 2, the buffered tiles are distributed to different processors for computing the local point density index in parallel. That tile-level parallel processing step is performed using a conventional algorithm with an R-tree data structure. While straight-forward, the proposed algorithm is efficient and particularly suitable for processing large point clouds. Experiments conducted using a 1.4 billion point data set acquired over part of Dublin, Ireland demonstrated an efficiency factor of up to 14.8/16. More specifically, the computational time was reduced by 14.8 times when the number of processes (i.e. executors) increased by 16 times. Computing the local point density index for the 1.4 billion point data set took just over 5 minutes with 16 executors and 8 cores per executor. The reduction in computational time was nearly 70 times compared to the 6 hours required without parallelism.

Objective: To analyse the care continuity across levels of care perceived by patients with chronic conditions in public healthcare networks in six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico and Uruguay), and to explore associated factors. Method: Cross-sectional study by means of a survey conducted to a random sample of chronic patients in primary care centres of the study networks (784 per country) using the questionnaire Cuestionario de Continuidad Asistencial Entre Niveles de Atención (CCAENA)©. Patients had at least one chronic condition and had used two levels of care in the 6 months prior to the survey for the same medical condition. Descriptive analysis and multivariable logistic regression were carried out. Results: Although there are notable differences between the networks analysed, the results show that chronic patients perceive significant discontinuities in the exchange of clinical information between primary care and secondary care doctors and in access to secondary care following a referral; as well as, to a lesser degree, regarding clinical coherence across levels. Relational continuity with primary care and secondary care doctors and information transfer are positively associated with care continuity across levels; no individual factor is systematically associated with care continuity. Conclusions: Main perceived discontinuities relate to information transfer and access to secondary care after a referral. The study indicates the importance of organisational factors to improve chronic patients’ quality of care. Resumen: Objetivo: Analizar la continuidad asistencial entre niveles de atención percibida por pacientes con enfermedades crónicas en redes sanitarias públicas de seis países latinoamericanos (Argentina, Brasil, Chile, Colombia, México y Uruguay) y explorar los factores asociados. Método: Estudio transversal mediante una encuesta realizada a una muestra aleatoria de pacientes crónicos en los centros de atención primaria de las redes de estudio (784 por país) utilizando el Cuestionario de Continuidad Asistencial Entre Niveles de Atención (CCAENA©). Los pacientes presentaban al menos una afección crónica y habían utilizado dos niveles de atención en los 6 meses anteriores a la encuesta por el mismo motivo. Se realizaron un análisis descriptivo y una regresión logística multivariante. Resultados: Aunque existen diferencias notables entre las redes analizadas, los resultados muestran que los pacientes crónicos perciben discontinuidades significativas en el intercambio de información clínica entre médicos de atención primaria y secundaria, y en el acceso a la atención secundaria tras una derivación, así como, en menor medida, en la coherencia clínica entre niveles. La continuidad de relación con los médicos de atención primaria y secundaria, y la transferencia de información, se asocian de manera positiva con la continuidad asistencial en ambos niveles; ningún factor individual se asocia sistemáticamente con la continuidad asistencial. Conclusiones: Las principales discontinuidades percibidas se relacionan con la transferencia de información y el acceso a la atención secundaria después de una derivación. El estudio indica la importancia de los factores organizativos para mejorar la calidad de la atención de los pacientes crónicos.

Abstract Background MSQOL-54 is a multidimensional, widely-used, health-related quality of life (HRQOL) instrument specific for multiple sclerosis (MS). Findings from the validation study suggested that the two MSQOL-54 composite scores are correlated. Given this correlation, it could be assumed that a unique total score of HRQOL may be calculated, with the advantage to provide key stakeholders with a single overall HRQOL score. We aimed to assess how well the bifactor model could account for the MSQOL-54 structure, in order to verify whether a total HRQOL score can be calculated. Methods A large international database (3669 MS patients) was used. By means of confirmatory factor analysis, we estimated a bifactor model in which every item loads onto both a general factor and a group factor. Fit of the bifactor model was compared to that of single and two second-order factor models by means of Akaike information and Bayesian information criteria reduction. Reliability of the total and subscale scores was evaluated with Mc Donald’s coefficients (omega, and omega hierarchical). Results The bifactor model outperformed the two second-order factor models in all the statistics. All items loaded satisfactorily (≥ 0.40) on the general HRQOL factor, except the sexual function items. Omega coefficients for total score were very satisfactory (0.98 and 0.87). Omega hierarchical for subscales ranged between 0.22 to 0.57, except for the sexual function (0.70). Conclusions The bifactor model is particularly useful when it is intended to acknowledge multidimensionality and at the same time take account of a single general construct, as the HRQOL related to MS. The total raw score can be used as an estimate of the general HRQOL latent score.